New interest has been awakened with respect to passive immunotherapy with activated lymphoid cells due to recent successes with LAK cells (lymphokine activated killer cells). For treatment, patients are administered IL-2 (interleukin-2) for priming and autologous cells are removed and activated ex vivo with IL-2. The activated cells, after a period of expansion, are then readministered to the patient along with IL-2 in order to maintain the lymphoid cells in an activated state. This form of therapy has been shown to be successful in both melanoma and renal cell cancer. In addition, numerous different schedules of IL-2 without LAK cells have been shown to enhance the production of endogenous circulating LAK cells. Other cell types, including PMNs and monocytes, can also be activated with a variety of lymphokines, including GM-CSF, G-CSF, gamma interferon, M-CSF, as well as TNF. With the discovery of colony-stimulating factors, the numbers of these cells can also be increased by enhancement of bone marrow progenitor survival. Thus, a variety of different cell types can be used for both passive as well as endogenous activated cell therapy.
However, a number of problems have been encountered which are typified by results with LAK cells. The first has to do with toxicity. Treatment with IL-2/LAK therapy or IL-2 alone has been shown to give rise to severe hypotension and edema. It has been recently demonstrated in vitro that nonspecificity of LAK cells may contribute to this toxicity. Second, studies with radiolabeled LAK cells, either derived from T or NK cells, have shown that these cells do not accumulate in tumors but primarily localize to RES (reticuloendothelial system) tissues. Thus, the mechanism of anti-tumor effect is not consistent with direct cytolytic action. Rather, these results are more consistent with effects caused by lymphokines secreted by the cells. Thus, in vitro studies which attempt to optimize direct cytolytic killing are probably not relevant to current clinical trials with LAK cells.
If one can increase tumor localization as well as reduce nonspecific binding to normal tissues, one can potentially improve therapy with these activated cells. Increased tumor localization will allow either direct cytolytic action or secretion of lymphokines in the region of the tumor as opposed to at a distance from the tumor. The specificity will assure that the direct cytolytic action is directed toward the appropriate target cells. Thus, enhanced localization and specificity of lymphoid cells is desired.